Correspondence

Plasma Therapy to Prevent Severe Covid-19 in Older Adults

To the Editor

Convalescent plasma therapy has shown a weak benefit in patients with severe or life-threatening Covid-19. However, when considering safety,1 some have advocated its use beyond this limited scope. Libster and colleagues (Feb. 18 issue)2 report positive results with the early administration of high-titer convalescent plasma against SARS-CoV-2 to mildly ill infected older adults. Although this randomized, controlled trial was limited in size (160 patients), it showed a 48% reduction in the relative risk of progression to severe respiratory disease.

Given the extraordinary humoral responses to SARS-CoV-2 vaccines3 and the paucity of donors with high-titer convalescent plasma (in our experience, <4% of samples obtained are high-titer), it is likely that the use of plasma from immunized donors can be of substantial benefit. Unfortunately, even though regulatory agencies have authorized the use of blood and platelet donations from immunized persons, they have also expressly prohibited the use of such donations for the treatment of Covid-19. Considering the worldwide availability of vaccinated populations and the great potential to reduce the number of patients with progression to severe disease, we believe that prompt authorization by regulatory agencies for emergency use would be in the best interest of society.

Fbio Klamt, Ph.D.
Federal University of Rio Grande do Sul, Porto Alegre, Brazil

Richard B. Parsons, Ph.D.
Kings College London, London, United Kingdom

Marcus H. Jones, M.D., Ph.D.
Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil

No potential conflict of interest relevant to this letter was reported.

This letter was published on May 12, 2021, at NEJM.org.

  1. 1. Joyner MJ, Bruno KA, Klassen SA, et al. Safety update: COVID-19 convalescent plasma in 20,000 hospitalized patients. Mayo Clin Proc 2020;95:1888-1897.

  2. 2. Libster R, Prez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med 2021;384:610-618.

  3. 3. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021;21:181-192.

To the Editor

Although we recognize that Libster et al. conducted this randomized trial under exceptional circumstances, we think the trial has several limitations that should be considered for its proper interpretation. First, the primary end point is a surrogate: severe disease is a substitute end point that has an uncertain relation to clinically important outcomes (e.g., mortality or mechanical ventilation).1 The primary end point was defined according to measurements with important variability over short periods of time (respiratory rate and oxygen saturation), which makes it vulnerable to outcome-measurement bias, especially when we consider that the members of the transfusion medicine team in charge of administering the intervention were aware of the treatment assignments.

Second, the estimate of the effect of the primary end point is fragile. The calculated fragility index is 1,2 which means that if results for one patient in the experimental group were changed from the patient not having the primary end point to the patient having the primary end point, the estimate of the effect would lose statistical significance.3 This issue becomes even more relevant when we consider that the trial was stopped early coincident with a large benefit.4 These limitations make it imperative that caution be used until adequately powered trials measuring critical outcomes confirm or disprove these findings.

Martin Ragusa, M.D.
Fernndez Hospital, Buenos Aires, Argentina

Fernando Tortosa, M.D.
Ministry of Health of Rio Negro, Rio Negro, Argentina

Ariel Izcovich, M.D., Ph.D.
Hospital Aleman de Buenos Aires, Buenos Aires, Argentina

No potential conflict of interest relevant to this letter was reported.

This letter was published on May 12, 2021, at NEJM.org.

  1. 1. Walter SD, Sun X, Heels-Ansdell D, Guyatt G. Treatment effects on patient-important outcomes can be small, even with large effects on surrogate markers. J Clin Epidemiol 2012;65:940-945.

  2. 2. Kane S. Fragility Index Calculator. ClinCalc, 2018 (https://clincalc.com/Stats/FragilityIndex.aspx).

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  3. 3. Walsh M, Srinathan SK, McAuley DF, et al. The statistical significance of randomized controlled trial results is frequently fragile: a case for a Fragility Index. J Clin Epidemiol 2014;67:622-628.

  4. 4. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA 2010;303:1180-1187.

Response

The authors reply: Klamt et al. emphasize the challenge of identifying enough persons with adequate concentrations of antibody in convalescent plasma against SARS-CoV-2 and the need to incorporate immunized volunteers into the donor pool worldwide. This problem was recently addressed by the Food and Drug Administration, which is allowing plasma donations from persons who had symptomatic Covid-19 and were subsequently immunized with vaccines available under emergency use authorization.1 The potential donors are easy to identify, are likely to understand well the physical and psychological burden of Covid-19 and be amenable to helping others, will rapidly have high titers of antibody in plasma2 (which could expand the pool of recipients if smaller volumes are used), and will have neutralizing antibody responses against new SARS-CoV-2 strains maintained by means of vaccination.3

We agree with Ragusa et al. that our trial was small, a circumstance that was driven by a challenging day-to-day situation at the hospitals and in the community. Rather than evaluating interventions in hospitalized patients to assess effects on mortality, we applied a well-established biologic principle for successful antibody therapy against viral illnesses: early treatment when patients had mild symptoms. The selection of mortality as the primary end point (assuming 5% mortality among placebo recipients) would have required the involvement of more than 1000 ill volunteers for the trial to show efficacy. This approach would have been impossible and consequently uninformative. (In fact, the trial was stopped early owing to the virtual disappearance of cases in the region.) We therefore preselected two biologic variables oxygen saturation and the respiratory rate, which were assessed by trained investigators who were unaware of the trial group assignments and who used calibrated equipment to evaluate the primary end point rather than relying on subjective strategies such as symptom assessment or on decisions influenced by bed availability, social considerations, or changing recommendations during the pandemic. We note that all the secondary end points, including life-threatening respiratory disease, critical systemic illness, and death, also trended toward benefit.

Finally, the fragility index analysis is focused on statistical significance, which is defined with the use of an arbitrary P value (i.e., 0.05). This approach has been criticized,4 and as recommended by the 2010 CONSORT (Consolidated Standards of Reporting Trials) statement,5 most journals, including the Journal, favor reporting results as effect sizes with confidence intervals, which allows the reader to assess the precision of the estimates and consequently gauge the clinical and public health significance of the trial in the context of the current emergency.

Diego Wappner, M.D.
Fundacin INFANT, Buenos Aires, Argentina

Eduardo Bergel, Ph.D.
Instituto de Efectividad Clnica y Sanitaria, Buenos Aires, Argentina

Fernando P. Polack, M.D.
Fundacin INFANT, Buenos Aires, Argentina

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on May 12, 2021, at NEJM.org.

  1. 1. Recommendations for investigational COVID-19 convalescent plasma. Silver Spring, MD: Food and Drug Administration. February 11, 2021 (https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma).

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  3. 3. Liu Y, Liu J, Xia H, et al. Neutralizing activity of BNT162b2-elicited serum. N Engl J Med 2021;384:1466-1468.

  4. 4. Wasserstein RL, Schirm AL, Lazar NA. Moving to a World Beyond p<0.05. Am Stat 2019;73:Suppl 1:1-19 (https://www.tandfonline.com/doi/full/10.1080/00031305.2019.1583913).

  5. 5. Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726-732.

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